Computing power of quantitative trait locus association mapping for haploid loci

<p>Abstract</p> <p>Background</p> <p>Statistical power calculations are a critical part of any study design for gene mapping. Most calculations assume that the locus of interest is biallelic. However, there are common situations in human genetics such as X-linked loci in males where the locus is haploid. The purpose of this work is to mathematically derive the biometric model for haploid loci, and to compute power for QTL mapping when the loci are haploid.</p> <p>Results</p> <p>We have derived the biometric model for power calculations for haploid loci and have developed software to perform these calculations. We have verified our calculations with independent mathematical methods.</p> <p>Conclusion</p> <p>Our results fill a need in power calculations for QTL mapping studies. Furthermore, failure to appropriately model haploid loci may cause underestimation of power.</p

Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p &lt; 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials

Genotype–phenotype correlation in PRKN- associated Parkinson’s disease

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials